tbuckley/cabot-search huggingface dataset:
A meta-analysis of local-regional therapy (LRT) in liver metastases from genitourinary cancers.
Authors: Murali Ranjani Behara, Dawood Findakly, Jue Wang
Journal: Journal of Clinical Oncology (2023)

e16606 Background: Liver metastases (Mets) from genitourinary cancers are difficult to treat and many of them are resistant to systemic therapy. Local-Regional Therapies (LRT) are becoming popular in treating Liver Mets. In this Meta-analysis, we analyze the outcomes of LRT for Liver Mets from Genitourinary Cancers. Methods: We searched PubMed, Google scholar for case reports, case studies, retrospective studies with patients who underwent LRT like Radiofrequency Ablation (RF), Chemoembolization (CE), Microwave Ablation (MA), Cryoablation for liver metastases for from Genitourinary Cancers including Prostate Cancer (PC), Testicular Cancer (TC) and Renal Cell Cancer (RCC). We also included 3 patients from Dignity Health Cancer Center, Phoenix, AZ. Results: Total number of patients in the study is 54, 3 of them from our Center. 39 are men and 15 are women. Mean and median age of the patients was 62.3, 65 years respectively. Number of patients with RCC, PC, TC are 43, 6, 5 respectively. 28 patients had CE, 23 had RFA and 3 had MA with the total number of procedures being 144, 41 and 5 respectively. Mean survival for all the patients is 62.7 months, mean survival for RCC, TC and PC are 68.9, 45.8 and 24.4 months respectively. Median number of systemic therapies received by the patients prior to getting LRT was 2 (range 1-4). We used RECIST criteria to quantify the benefit from LRT, 23 patients had Complete Response (CR), 6 had Partial Response (PR), 14 had Stable Disease (SD) and 8 had Progressive Disease (PD), there was no data for 2 patients. 43 patients had Clinical Benefit. We present a case of castration resistant metastatic PC from our facility. A 78-year man diagnosed metastatic PC in 2007 who had Prostatectomy, salvage radiation, intermittent androgen deprivation and Combined deprivation therapy. But his PSA continued to rise, flutamide was added. In 2017, he had liver metastasis, had RFA twice for 2 liver lesions and had CR. He continues to be on relugolix with good quality of life. Patients in the study are people with advanced metastatic cancer who underwent various systemic therapies like chemotherapy, radiation, immunotherapy and hormonal therapy prior to getting the LRT. LRT was done as the patients failed or did not tolerate systemic therapies. The mean survival for RCC patients in the study group is greater than the average survival of stage IV RCC, the lower mean survival for PC and TC can be explained by the limited number of this patient population in the study. Conclusions: Combination of LRT with systemic therapy for previously heavily treated Liver Mets from genitourinary cancers is a promising strategy for patients with otherwise poor prognosis. [Table: see text]
A multicenter study on adjuvant chemotherapy of S-1 versus observation for resected perihilar cholangiocarcinoma.
Authors: Isamu Hosokawa, Ryota Higuchi, Yuki Homma, Tsukasa Takayashiki, Yusuke Ome, Ryusei Matsuyama, Shigetsugu Takano, Shuichiro Uemura, Yasuhiro Yabushita, Daisuke Suzuki, Kentaro Miyake, Goro Honda, Itaru Endo, Masayuki Ohtsuka
Journal: Journal of Clinical Oncology (2023)

e16201 Background: The prognosis of perihilar cholangiocarcinoma (PHC) is poor even after curative resection. The efficacy of adjuvant S-1 chemotherapy for resected PHC is unclear. This study aimed to assess the efficacy of adjuvant S-1 chemotherapy after major hepatectomy for PHC. Methods: Consecutive patients with PHC who underwent major hepatectomy (hemihepatectomy or trisectionectomy extending to segment 1 with extrahepatic bile duct resection) at three high-volume centers in Japan from 2007 to 2020 were retrospectively evaluated. Patients with Clavien-Dindo grade V complications, pStage I or IVB disease, and those who underwent adjuvant radiation therapy were excluded from analysis. Propensity score matching analysis was performed to compare the disease-specific survival (DSS) of patients who underwent adjuvant S-1 chemotherapy with those who underwent observation. Results: Of 480 patients, 373 were eligible for the study, 81 of whom underwent adjuvant S-1 chemotherapy, and 146 underwent observation. In the global cohort, DSS in the S-1 and observation groups were similar ( P = 0.18). In the matched cohort as well (S-1: n=44, Observation: n=44), DSS was similar between the S-1 and observation groups ( P = 0.09). On multivariate analysis, performance of percutaneous biliary drainage, CA19-9 levels at operation ≥ 300 U/ml, and lymph node (LN) metastasis were independent predictors of poor survival following major hepatectomy for PHC. In subgroup analysis of patients with LN metastasis, DSS in the S-1 group was better than in the observation group ( P = 0.001). Conclusions: Adjuvant S-1 chemotherapy after major hepatectomy might be effective in PHC patients with LN metastasis.
Frequency of delayed immune-related adverse events (irAEs) in hospitalized patients treated with immune checkpoint inhibitors (ICIs).
Authors: Sienna Durbin, Leyre Zubiri, Katherine Perlman, Gabriel Molina, Ted Jacoby, Nishi Shah, Kerry Lynn Reynolds
Journal: Journal of Clinical Oncology (2023)

2652 Background: Across cancer types and indications, the use of ICIs is increasing. Guidelines indicate that most irAEs occur in the months immediately following receipt of ICI. Little is known about the frequency of delayed irAEs following ICI administration. Methods: Patients who received ICIs and were hospitalized following ICI initiation between January 2011 and October 2022 were identified using pharmacy and hospital admission databases. Patient demographics, and oncologic and irAE history were extracted from the medical record. All admissions were reviewed by two physicians to evaluate for irAEs, which were defined as suspected or confirmed using published disease-specific criteria. We examined the number of irAEs hospitalizations at &lt; 6 months, 6-12 months, 1-2 years, 2-5 years, and &gt;5 years from the first dose of the most recent line of ICI to date of admission. Results: Among the 930 patients hospitalized with irAEs, average age was 66.0 years (range 18.3 - 96.2) and 61.2% were male. Most common tumor types were melanoma (42.0%), lung (24.1%), and gastrointestinal (12.7%). Median time from start of last line of ICI to hospitalization was 98 days (IQR 37-244.3). One hundred sixty-six patients (19.4%) had been treated with &gt;1 prior line of ICI and 102 (11.0%) were diagnosed with multiple irAEs during the same admission. Of all patients admitted, 147 (15.7%) presented 6 months – 1 year after start of ICI line, 79 (8.4%) presented after 1-2 years, 35 (3.7%) presented after 2-5 years, and 2 (0.2%) presented after &gt;5 years. Rates of irAEs by time from start of ICI line are demonstrated. Conclusions: Although irAEs occur in a time-dependent fashion, delayed, serious irAEs in hospitalized patients are common (28% at 6+ months), with a subset presenting two years or more after start of ICI. Providers must remain vigilant for potential irAEs regardless of elapsed time from ICI, especially as patients live longer and ICIs become widely used in different settings. Future work is needed to define potential triggers of and patients at risk for delayed irAEs. [Table: see text]
A phase II study of olaparib and durvalumab in patients with IDH-mutated cholangiocarcinoma.
Authors: Erica S. Tsang, Grainne M. O'Kane, Jennifer J. Knox, Eric X Chen
Journal: Journal of Clinical Oncology (2023)

4099 Background: IDH1/2 mutations (m) occur in approximately 25% of cholangiocarcinomas (CCAs) (20% intrahepatic, &lt; 5% extrahepatic) and result in the accumulation of R-2-hydroxyglutarate (R2HG). R2HG, suppresses homologous recombination repair and as a result IDH1/2m are hypothesized to predict PARP inhibitor sensitivity. PARP inhibition upregulates PD-L1 and the combination is thought to be synergistic. We conducted a phase II trial of olaparib with durvalumab for patients with IDH-mutated cholangiocarcinoma. Methods: Patients with advanced IDHm CCA were enrolled in this phase II open-label study (NCT03991832). Patients received olaparib 300 mg twice daily continuously and durvalumab 1500 mg IV every 4 weeks. Simon’s optimal two-stage design was used, with an interim analysis planned for efficacy. 10 patients were accrued in the first stage, with a plan for expansion if ≥2 responses were observed. The primary objective was to determine the overall response rate (RECIST 1.1) and disease control rate (DCR). Secondary objectives included progression-free survival, overall survival, and safety of the olaparib and durvalumab combination. Results: 10 patients with IDH1m were enrolled in this study between January 2020-August 2021. Median age was 63.5 years (range 49-78), and 50% were female. All patients had a baseline ECOG PS of 0-1. 40% of patients had prior surgical resections and subsequently developed recurrent disease. 20% of patients had ³2 lines of prior chemotherapy, with 90% receiving prior platinum. Median duration of treatment was 1.95 months (range 1.8-13.5). There were no treatment-related grade 3-4 toxicities. Any grade toxicities included fatigue (100%), nausea (60%), anemia (20%), hypothyroidism (20%), elevated liver enzymes (20%). We did not observe any complete or partial responses. The DCR was 30% with 3 patients demonstrating stable disease. One patient remained on treatment for 13.5 months, and was eventually taken off study due to clinical progression. The median PFS was 1.97 months (95% CI 1.73-3.93). Given that no responses were seen in the initial 10 patients, the study did not proceed to Stage 2. Conclusions: While the combination of olaparib and durvalumab was well-tolerated, this study was discontinued after Stage I due to lack of efficacy. IDH1/2m may not induce a BRCAness phenotype and further correlative studies are planned to evaluate this. Clinical trial information: NCT03991832 .
Renal cell carcinoma with metastasis to the pancreas: Genomic signatures and clinical outcomes.
Authors: Michael Glover, Ryan S. Chiang, Christian R. Hoerner, Osama A. Khan, Chia-Sui Kao, Sumit Shah, Sandy Srinivas, Alice C. Fan, Ali Raza Khaki
Journal: Journal of Clinical Oncology (2023)

e16519 Background: Renal cell carcinoma (RCC) is a diverse disease characterized by several subtypes, mutations, and a broad spectrum of sites of metastasis. Previous publications have established that RCC with pancreatic metastases (PM), a rare subpopulation, has more favorable outcomes, even when other metastases sites are involved. Outcomes in this subpopulation tend to be independent of the traditional IMDC risk stratification. We have previously explored the genomic landscape of RCC with PM. In this analysis, we explore the clinical data and correlation with NGS for a subset of patients treated at our institution. Methods: We identified patients (pts) at our institution with metastatic RCC with PM. Included pts had pathologically confirmed RCC with met to pancreas seen on imaging. All identified pts had NGS performed with Tempus xT assay (DNA-seq of 648 genes at 500x coverage). We also extracted demographic, clinicopathologic, and treatment data for included pts through chart review. We describe baseline characteristics, most prevalent gene mutations on xT and overall survival (OS) from time of diagnosis to death with particular attention of OS stratified by PBRM1 mutation. We also performed a log rank test to compare OS for those with and without PBRM1 mutation. Results: 23 pts with metastatic RCC with PM were identified. Pts included were diagnosed with RCC between 1993 and 2020, median age was 62 years (range 42-78), 48% were female, 70% of white race, 35% with smoking history. All patients had a nephrectomy and 91% had clear cell histology. 6 pts (26%) had de novo metastatic disease (3 [14%] with de novo PM). Median time to metastatic disease was 3.5 years (range 0-15.5 years) and median time to PM was 4.7 years (range 0-15.5 years). The most prevalent genes identified with mutations were VHL (70%), PBRM1 (39%), and SETD2 (32%); TP53 mutations were identified in 2 pts (9%). After a median follow-up of 16 years, 10 pts (43%) were deceased (7 due to RCC, 3 due to other causes), 11 pts were alive (5 without disease and 6 with active disease) and 2 with unknown vital status. Median [m]OS for the whole cohort was 12.7 years, which when stratified by PBRM1 mutation was 8.4 and 12.7 years for those with and without PBRM1 mutation, respectively, though this difference was not statistically significant. Conclusions: In our cohort, patients with RCC and PM had an indolent course with a prolonged survival even after diagnosis of metastatic disease. This effect was independent of PBRM1 mutations or other common mutations. As these patients presented with both de novo PM as well as later in the course, this may represent a unique population, rather than a result of survival bias.
Analysis of survival outcomes in patients with non–small-cell lung cancer with mutations in STK11/LKB1 receiving chemoimmunotherapy.
Authors: Diana Kim, Rachel Elsey, Tobias Meissner, Yuliang Sun, Bing Xu, Crystal Hattum, Benjamin Maurice Solomon, John H. Lee, Casey B. Williams
Journal: Journal of Clinical Oncology (2023)

e15043 Background: Many patients with non-small-cell lung cancer (NSCLC) do not benefit from first-line treatment with immune checkpoint inhibitors (ICI) alone or in combination with chemotherapy due to resistance or toxicity. In NSCLC, significant research has been undertaken to provide prognostic markers for single agent immune checkpoint inhibitor therapy. Co-alterations in TP53, STK11/LKB1 and KRAS have a low reported prevalence in NSCLC, however, potentially may represent a distinct molecular subtype of NSCLC that conveys primary resistance to single-agent ICI. Data continues to accumulate regarding resistance mechanisms to ICI, but limited data exists exploring these alterations and the corresponding survival outcomes in patients that receive chemoimmunotherapy. The primary objective of this study was to assess the association between alterations and co-alterations in STK11/LKB1 and survival outcomes in patients with NSCLC receiving chemo-immunotherapy. Methods: This was a retrospective study of patients ≥18 years old who had completed NGS testing and had a diagnosis of non-small-cell lung cancer that received chemoimmunotherapy from January 2016 to November 2022. NGS reports were reviewed to assess the status of STK11/LKB1, KRAS, KEAP1, and TP53 alterations. Additional markers assessed were PD-L1 status, TPS, CPS, TMB, and MSI if available. Results: Sixty-five patients were identified who had received chemoimmunotherapy for NSCLC, had NGS testing results, and were considered to be evaluable for retrospective review. Four patients were identified with co-altered KRAS, STK11, and TP53, and this alone was not significant for PFS (p= 0.48) or OS (p = 0.52) compared to patients without the alterations, however patients with the co-alterations and a positive PD-L1 showed an improvement in PFS (p =0.053). Patients with altered STK11, including those classified as VUS, had a poorer OS (p = 0.088). Our analysis also showed that PD-L1 negative patients had poorer OS (p = 0.088). Conclusions: The addition of chemotherapy to ICI may overcome resistance previously described in NSCLC patients with co-alterations in KRAS, STK11, and TP53, who received single-agent ICI and these genomic findings should not deter from the use of chemoimmunotherapy based on our limited experience. Patients with alterations in STK11 did have poorer outcomes overall, which is in line with previously published data describing STK11 as a poor prognostic marker in NSCLC. STK11 alterations have previously been described to be associated with PD-L1 negativity which may explain, at least in part, the poorer responses in the STK11 mutated subgroup.
Use of proton pump inhibitors (PPI) in glioblastoma (GBM) and relationship to overall survival in a national real-world evidence (RWE) database.
Authors: Michael P Castro, Jameson Quinn, Asher Wasserman, Mark Adam Shapiro, Timothy Joseph Stuhlmiller, Santosh Kesari
Journal: Journal of Clinical Oncology (2023)

e14027 Background: Aldehyde dehydrogenase-1A1 ( ALDH1A1) mediates therapy resistance and poor prognosis in multiple cancers. In GBM, ALDH1A1 expression above vs. below the mean is associated with a significant reduction in survival. 1 ALDH enzymes activate transcriptional programs that induce the cancer stem cell phenotype, detoxify anticancer drugs, and function as antioxidants by reversing lipid peroxidation and etheno-DNA adducts, thus conferring chemotherapy and radiation resistance. PPI have been shown to increase enzyme activity of ALDH1A1 up to 6-fold, suggesting a potentially hazardous effect on tumor biology and survival. However, no prospective randomized data are available to address these concerns. Thus, we turned to XCELSIOR, an observational database that prospectively collects medical records including medication usage. Methods: Patients with GBM were e-consented to XCELSIOR ( NCT03793088 ), a nationwide observational research protocol that leverages patient consent to permit gathering of medical records from all sites of care. Clinical data were abstracted from medical documents into a central EDC system, source-verified, and standardized to generate comprehensive longitudinal histories for aggregate analysis. Identified patient records permitted the definitive identification of dates of diagnosis and death. Overall survival (OS) was calculated and stratified based for PPI exposure, extent of surgical resection (EOR), and MGMT methylation status. Results: XCELSIOR contained 320 GBM patients from 222 treatment sites. We stratified patients based on exposure to PPI and assessed median OS (mOS). For the entire population, mOS was substantially better for patients not receiving PPI. (TABLE) The 5-yr survival was 29.9% [21.0 – 42] and 6.6% [1.4 – 32.0] for patients not receiving vs. receiving PPI. In a multivariate analysis considering EOR and MGMT methylation, PPI exposure yielded a hazard ratio (HR) of 1.57 (p=0.009). For the interaction of m-MGMT and PPI exposure together, the HR is 2.63 (p=0.043), significant as the HR of m-MGMT alone is 0.40 (p=0.0028). Conclusions: In this RWE dataset, PPI use in GBM appeared detrimental to survival. This is strongly consistent with the hypothesis that PPI antagonizes chemotherapy. Additionally, use of PPI appeared to completely abrogate the survival benefit of chemotherapy associated with methylated-MGMT. While we recognize the utility of PPI in managing acute UGI bleeding, these data suggest avoiding PPIs in GBM patients. 1) Schmidt-Graf F, et al. Neuro Oncol. 2012;14(12):1452–1464. [Table: see text]
Donafenib combined with anti-PD-1 antibody and transarterial chemoembolization (TACE) as first-line (1L) treatment for unresectable/advanced hepatocellular carcinoma (HCC).
Authors: Jian Zhou, Zhiping Yan, Zheng Wang, Shuang-Jian Qiu, Minjie Yang, Kai Zhu, Yong Yi, Lei Yu, Yun-Fan Sun, Bo Zhang, Jiaze Yu
Journal: Journal of Clinical Oncology (2023)

e16107 Background: Targeted drugs, immune checkpoint inhibitors and TACE are important non-surgical approaches to treat HCC. A triple combination of the three is under investigation. This prospective study was conducted to assess the efficacy and safety of donafenib combined with anti-PD-1 antibody and TACE as first-line treatment for unresectable or advanced HCC. Methods: Patients (pts) who had histologically or clinically confirmed HCC and with no prior systemic therapy, at least one measurable lesion per mRECIST, Child-Pugh score ≤7, and ECOG PS score 0-1 were enrolled and received donafenib 100 mg twice daily, anti-PD-1 antibody Q3W and on-demand conventional TACE. CT/MRI scans were performed every six weeks. The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival and safety. Results: A total of 30 pts were enrolled between Dec 2021 and Nov 2022. All pts had HBV-related HCC and baseline ECOG PS score of 0. Baseline characteristics are shown in the Table. As of 6 Feb 2023, eleven pts had discontinued the triple therapy. The median follow up time was 3.6 months (range, 1.8-13.4). The median number of on-study TACE sessions was 2 (range, 1-4). Among 29 efficacy evaluable pts, five pts had disease progression and no death occurred. The median PFS was not reached (95%CI, 2.4 months -NE). The 6-month PFS rate was 69.4% (95%CI, 34.5%-84.0%). Five pts had a complete response and 13 had a partial response (responders). ORR and DCR were 62.1% (95%CI, 42.3%-79.3%) and 86.2% (95%CI, 68.3%-96.1%) per mRECIST. The median time to response was 1.3 months (95%CI, 1.1-1.6). The median duration of response was not reached (95%CI, 3.4 weeks-NE). Four pts (1 with BCLC B, 3 with BCLC C) underwent successful surgical resection after a median treatment duration of 2.9 months (range, 1.8-3.3) and no recurrence was noted with a median of 5.9 months (range, 2.8-10.2) follow-up after hepatectomy. In the safety population (n = 30), any grade and grade 3 treatment-related adverse events (TRAEs) occurred in 15 (50.0%) and 7 (23.3%) pts with no grade 4 TRAEs or toxic death. Rash was the most common grade 3 TRAE (incidence: 13.3%) and led to treatment discontinuation in one pt. Conclusions: The triple combination of donafenib plus anti-PD-1 antibody and TACE showed promising efficacy and was well tolerated in pts with unresectable or advanced HCC. Clinical trial information: NCT05262959 . [Table: see text]